title: Skin microbiome imbalance in patients with STAT1/STAT3 defects impairs innate host defense responses.
abstract: BACKGROUND
  Chronic mucocutaneous candidiasis (CMC) and hyper-IgE syndrome (HIES) are primary immunodeficiencies mainly caused by mutations in STAT1 and STAT3, respectively. CMC and HIES patients have an increased risk for skin and mucosal infections with fungal pathogens and Staphylococcus aureus. However, it is unknown whether the genetic defects in these patients also affect the skin and mucosal microbiome, which in turn may influence host defense mechanisms.
  
  
  METHODS
  The skin and oral microbiome of CMC and HIES patients was compared to that of healthy controls at five body sites using 16S rRNA sequencing. The influence of skin colonizers on the immune response was investigated using in vitro experiments.
  
  
  RESULTS
  The microbiome of CMC and HIES patients contained more Gram-negative bacteria, especially Acinetobacter spp., and less of the normal Corynebacterium spp. compared to healthy controls. Exposure of human primary leukocytes to Acinetobacter suppressed the cytokine response to Candida albicans and S. aureus, while the normal corynebacteria did not suppress cytokine responses.
  
  
  CONCLUSIONS
  These results demonstrate that central mediators of immune responses like STAT1 and STAT3 not only directly influence immune responses, but also result in changes in the skin microbiome that in turn can amplify the defective immune response against fungal and microbial pathogens.
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Sanne P
authors.initials: SP
authors.lastname: Smeekens
authors.forename: Curtis
authors.initials: C
authors.lastname: Huttenhower
authors.forename: Anca
authors.initials: A
authors.lastname: Riza
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.forename: Patrick L J M
authors.initials: PL
authors.lastname: Zeeuwen
authors.forename: Joost
authors.initials: J
authors.lastname: Schalkwijk
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Dirk
authors.initials: D
authors.lastname: Gevers
mesh_terms: D000150:Acinetobacter / Q000235:genetics / Q000276:immunology*; D000328:Adult; D001424:Bacterial Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D002176:Candida albicans / Q000276:immunology*; D002178:Candidiasis, Chronic Mucocutaneous / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D002478:Cells, Cultured; D003352:Corynebacterium / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007165:Immunosuppression Therapy; D007589:Job Syndrome / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000382:microbiology; D008213:Lymphocyte Activation; D008297:Male; D064307:Microbiota / Q000235:genetics; D008875:Middle Aged; D009055:Mouth / Q000276:immunology* / Q000382:microbiology; D009154:Mutation / Q000235:genetics; D012336:RNA, Ribosomal, 16S / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics; D017422:Sequence Analysis, DNA; D012867:Skin / Q000276:immunology* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000276:immunology*
chemical_list: D016207:Cytokines; D012336:RNA, Ribosomal, 16S; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor